Pneumococcal disease caused by the bacterium Streptococcus pneumoniae (also known as pneumococcus) is one of the more important bacterial pathogens across globe. The disease burden is high in the developing countries in children under five years of age where the vaccine is not available. Pneumococcal disease is a complex group of illnesses and includes invasive infections such as bacteremia/sepsis, meningitis, pneumonia and otitis media, which affects both children and adults. Prevnar 13 (also known as “Prevenar 13” and referred to herein as “Prev(e)nar 13”) is a formulation of polysaccharides from thirteen pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F)) which are individually conjugated to CRM197 (Cross Reactive Material from a mutant strain of Corynebacterim diphtheriae). Prev(e)nar 13 is recommended for active immunization of infants and toddlers to provide the broadest serotype coverage of any pneumococcal conjugate vaccines. Notably, serotype 19A in Prev(e)nar 13 is prevalent in many regions of the world and is often associated with antibiotic resistance. See e.g., WO2006/110381; WO2008/079653; WO2008/079732; WO2008/143709 and references cited therein.
Thimerosal (also known as Thiomersal; merthiolate) is an ethylmercury-containing preservative which has, since the early 1930s, been added to many multi-dose injectable formulations and topical solutions to protect them from potential contamination during exposure and when administered to multiple subjects. Thimerosal continues to be administered, as part of mandated immunizations and in other pharmaceutical products in the United States and the rest of the world. It is claimed to be an effective preservative for eliminating potential contaminating bacteria during multiple use of products in the field, with minimum interaction with the antigenic structure and properties of vaccines. Due to mounting controversies regarding potential safety issues and adverse effects of ethylmercury on brain development in infants and youth, certain agencies began recommending that alternative preservatives with a lower or negligible safety risk be identified. In 1999, a U.S. Food and Drug Administration review mandated by the U.S. Congress found that some infants might receive more mercury from vaccines than was considered acceptable according to certain national guidelines. The American Academy of Pediatrics (AAP) and US Public Health Service (USPHS) issued a joint statement concerning Thimerosal in vaccines and then the AAP released an interim report to clinicians recommending removal of Thimerosal from vaccines as soon as possible, while maintaining efforts to ensure high levels of vaccination continue to be implemented worldwide without affecting safety.
The need for adding preservatives to vaccines can be reduced or obviated by making and using only single-dose vaccine formulations. However, use of single-dose preservative-free formulations raises the overall cost of vaccination and jeopardizes the effectiveness of immunization programs in developing countries. In addition, removing preservatives from multi-dose vials altogether is not viewed as a preferred option, especially in countries with limited cold storage and suboptimal standards of health care (Drain et al., Bull World Health Organ 81(10): 726-731 (2003). In 1928, twelve out of 21 children inoculated with contaminated diphtheria vaccine died of multiple staphylococcal abscesses and toxemia (Wilson, The Hazards of Immunization, Athlone Press, London. pp. 75-78 (1967). Thus, although multi-dose vials appear to be most appropriate for the production of less expensive vaccines, it is desirable to formulate multi-dose vaccines with at least one preservative to protect subjects from micro-organisms inadvertently introduced into the vaccine during multiple uses or after one or more non-sterile events. The efficacy of preservatives in resisting bacterial and other micro-organism contaminations must be balanced, however, with the effect that a particular preservative has on the immunogenicity as well as on the long term stability of each different antigenic determinant in an immunogenic composition of choice. The compatibility of Prev(e)nar 13 formulations with preservatives has not been previously addressed. It would be desirable to have an optimized formulation comprising at least one preservative that protects and/or stabilizes antigenic determinants of the pneumococcal antigen serotypes present in Prev(e)nar 13.